This application claims benefit of priority to EP Application no. 00105514.4, filed Mar. 15, 2000, and EP Application no. 00125169.3, filed Nov. 18, 2000, both of which are incorporated herein by reference.
The present invention relates to novel substituted beta-carbolines, a process for their preparation and use thereof as pharmaceuticals.
Art related to the present invention includes U.S. Pat. Nos. 4,631,149 and 5,604,236. U.S. Pat. No. 4,631,149 discloses beta-carbolines useful as antiviral, antibacterial and antitumor agents. U.S. Pat. No. 5,604,236 discloses beta-carboline derivatives containing an acidic group, useful as thromboxane syntheses inhibitors.
NFkB is a heterodimeric transcription factor which can activate a large number of genes which code, inter alia, for proinflammatory cytokines such as IL-1, IL-2, TNFxcex1 or IL-6. NFkB is present in the cytosol of cells, building a complex with its naturally occurring inhibitor IkB. The stimulation of cells, for example by cytokines, leads to the phosphorylation and subsequent proteolytic degradation of IkB. This proteolytic degradation leads to the activation of NFkB, which subsequently migrates into the nucleus of the cell and there activates a large number of proinflammatory genes.
In disorders such as rheumatoid arthritis (in the case of inflammation), osteoarthritis, asthma, cardiac infarct, Alzheimer""s disease or atherosclerosis, NFkB is activated beyond the normal extent. Inhibition of NFkB is also of benefit in cancer therapy, since it is employed there for the reinforcement of the cytostatic therapy. It has been shown that pharmaceuticals such as glucocorticoids, salicylates or gold salts, which are employed in rheumatic therapy, intervene in an inhibitory manner at various points in the NFkB-activating signal chain or interfere directly with the transcription of the genes.
The first step in the signal cascade mentioned is the degradation of IkB. This phosphorylation is regulated by the specific IkB kinase. To date, no inhibitors are known which specifically inhibit IkB kinase.
In the attempt to obtain active compounds for the treatment of rheumatoid arthritis (in the case of inflammation), osteoarthritis, asthma, cardiac infarct, Alzheimer""s disease, carcinomatous disorders (potentiation of cytotoxic therapies) or atherosclerosis, the inventors have surprisingly discovered that the benzimidazoles of the present invention are strong and very specific inhibitors of IkB kinase.
The invention therefore relates to the compounds of the formula I 
and/or a stereoisomeric form of the compounds of the formula I and/or a physiologically tolerable salt of the compounds of the formula I, where B6, B7, B8 and B9 are independently selected from the group consisting of carbon atom and nitrogen atom, where B6, B7, B8 and B9 together comprise no more than two nitrogen atoms; wherein
in case a)
the substituents R1, R2 and R3 may be independently chosen from:
1.1. hydrogen atom,
1.2. halogen,
1.3. xe2x80x94CN,
1.4. xe2x80x94COOH,
1.5. xe2x80x94NO2,
1.6. xe2x80x94NH2,
1.7. xe2x80x94Oxe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from:
1.7.1 phenyl, which is unsubstituted or mono- to penta-substituted by substituents independently chosen from halogen or xe2x80x94Oxe2x80x94(C1-C4)-alkyl,
1.7.2 halogen,
1.7.3 xe2x80x94NH2,
1.7.4 xe2x80x94OH,
1.7.5 xe2x80x94COOR16, wherein R16 is hydrogen atom or xe2x80x94(C1-C10)-alkyl,
1.7.6 xe2x80x94NO2,
1.7.7 xe2x80x94S(O)yxe2x80x94R14, wherein y is zero, 1 or 2, R14 is xe2x80x94(C1-C10)-alkyl, phenyl, which phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those defined under 1.7.1 to 1.7.11, amino or xe2x80x94N(R13)2, wherein R13 is independently of one another chosen from hydrogen atom, phenyl, xe2x80x94(C1-C10)-alkyl, xe2x80x94C(O)xe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)-phenyl, xe2x80x94C(O)xe2x80x94NHxe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)xe2x80x94O-phenyl, xe2x80x94C(O)xe2x80x94NH-phenyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C7)-alkyl,
xe2x80x94S(O)yxe2x80x94R14, wherein R14 and y are as defined above,
and wherein the R13 alkyl or phenyl groups in each case are unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, or
R13 together with the nitrogen atom to which it is bonded may be independently chosen to form a heterocycle having 5 to 7 ring atoms,
1.7.8 xe2x80x94O-phenyl, wherein phenyl is unsubstituted or mono- to penta-substituted independently of one another as defined under 1.7.1 to 1.7.11,
1.7.9 a radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine,
1.7.10 xe2x80x94(C3-C7)-cycloalkyl or
1.7.11 xe2x95x90O,
1.8. xe2x80x94N(R13)2, wherein R13 is as defined in 1.7.7 above,
1.9. xe2x80x94NHxe2x80x94C(O)xe2x80x94R15, wherein R15 is
1.9.1 a radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine,
wherein said radical is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, by xe2x80x94CF3, by benzyl or by xe2x80x94(C1-C10)-alkyl, wherein the xe2x80x94(C1-C10)-alkyl is mono to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
1.9.2 xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above or by xe2x80x94Oxe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
1.9.3 xe2x80x94(C3-C7)-cycloalkyl,
1.9.4 xe2x80x94N(R13)2, wherein R13 is as defined in 1.7.7 above, or
1.9.5 phenyl, wherein phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, by xe2x80x94Oxe2x80x94(C1-C10)-alkyl, by xe2x80x94CN, by xe2x80x94CF3, by xe2x80x94(C1-C10)-alkyl, wherein alkyl is mono to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, or by two substituents of said phenyl which form a dioxolan ring,
1.10. xe2x80x94S(O)yxe2x80x94R14, wherein R14 and y are as defined in 1.7.7 above,
1.11. xe2x80x94C(O)xe2x80x94R12, wherein R12 is phenyl or xe2x80x94(C1-C7)-alkyl, wherein alkyl or phenyl are unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under
1.7.1 to 1.7.11 above,
1.12. xe2x80x94C(O)xe2x80x94Oxe2x80x94R12, wherein R12 is as defined in 1.11. above,
1.13. xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
1.14. xe2x80x94Oxe2x80x94(C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl,
1.15. xe2x80x94Oxe2x80x94(C0-C4)-alkyl-(C3-C7)-cycloalkyl,
1.16. xe2x80x94(C1-C4)-alkyl-N(R13)2, wherein R13 is as defined in 1.7.7 above
1.17. xe2x80x94CF3 or
1.18. xe2x80x94CF2xe2x80x94CF3,
R4 is 1. xe2x80x94(C1-C10)-alkyl, wherein alkyl is mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
2. xe2x80x94CF3,
3. xe2x80x94CF2xe2x80x94CF3,
4. xe2x80x94CN,
5. xe2x80x94S(O)yxe2x80x94R14, wherein R14 and y are as defined in 1.7.7 above,
6. xe2x80x94NH2,
7. xe2x80x94Oxe2x80x94(C1-C10)-alkyl, wherein alkyl is mono- to penta-substituted by substituents independently chosen from
7.1 phenyl, which is unsubstituted or mono- to penta-substituted by substituents independently chosen from halogen or xe2x80x94Oxe2x80x94(C1-C4)-alkyl,
7.2 halogen,
7.3 xe2x80x94NH2,
7.4 xe2x80x94OH,
7.5 xe2x80x94COOR16, wherein R16 is hydrogen atom or-(C1-C10)-alkyl,
7.6 xe2x80x94NO2,
7.7 xe2x80x94S(O)xe2x80x94R14, wherein y is zero, 1 or 2, R14 is xe2x80x94(C1-C10)-alkyl, phenyl, which phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, amino or xe2x80x94N(R13)2,
wherein R13 is independently of one another chosen from hydrogen atom, phenyl, xe2x80x94(C1-C10)-alkyl, xe2x80x94C(O)xe2x80x94(C1-C7)-alkyl, C(O)-phenyl, xe2x80x94C(O)xe2x80x94NHxe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)-O-phenyl, xe2x80x94C(O)xe2x80x94NH-phenyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C7)-alkyl, xe2x80x94S(O)yxe2x80x94R14, wherein R14 and y are defined as in 7.7,
and wherein the R13 alkyl or phenyl groups in each case are unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, or
R13 together with the nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
7.8 xe2x80x94O-phenyl, wherein phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
7.9 a radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, thiophene, 2-isoxazoline, isothiazolidine, 2-isothiazoline, or thiomorpholine,
7.10 xe2x80x94(C3-C7)-cycloalkyl or
7.11 xe2x95x90O,
8. xe2x80x94N(R17)2, wherein R17 is independently of one another chosen from hydrogen atom, phenyl, xe2x80x94(C1-C10)-alkyl, xe2x80x94C(O)-phenyl, xe2x80x94C(O)xe2x80x94NHxe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)xe2x80x94(C1-C10)-alkyl, xe2x80x94C(O)xe2x80x94O-phenyl, xe2x80x94C(O)xe2x80x94NH-phenyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C7)-alkyl, xe2x80x94S(O)yxe2x80x94R14, wherein R14 and y are as defined as in 7.7 above,
and wherein alkyl or phenyl in each case are unsubstituted or mono- to penta-substituted independently of one another as defined under 1.7.1 to 1.7.11 above, or
R17 together with the nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
9. xe2x80x94NHxe2x80x94C(O)xe2x80x94R15, wherein R15 is
9.1 a radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine,
wherein said radical is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, xe2x80x94CF3, benzyl or by xe2x80x94(C1-C10)-alkyl, wherein alkyl is mono to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
9.2 xe2x80x94(C1-C10)-alkyl, wherein alkyl is mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above or by xe2x80x94Oxe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
9.3 xe2x80x94(C3-C7)-cycloalkyl,
9.4 xe2x80x94N(R13)2, wherein R13 is as defined in 1.7.7 above provided that
xe2x80x94N(R13)2 is not xe2x80x94NH2, or
9.5 phenyl, wherein phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, by xe2x80x94Oxe2x80x94(C1-C10)-alkyl, by xe2x80x94CN, by xe2x80x94CF3, by xe2x80x94(C1-C10)-alkyl, wherein alkyl is mono to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, or by two substituents of the phenyl radical which form a dioxolan ring
10. xe2x80x94C(O)xe2x80x94R12, wherein R12 is phenyl or xe2x80x94(C1-C7)-alkyl, wherein phenyl or alkyl are mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
11. xe2x80x94C(O)xe2x80x94Oxe2x80x94R2, wherein R12 is as defined in 10, above,
12. xe2x80x94Oxe2x80x94(C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl,
13. xe2x80x94Oxe2x80x94(C0-C4)-alkyl-(C3-C7)-cycloalkyl or
14. xe2x80x94(C1-C4)-alkyl-N(R13)2, wherein R13 is as defined in 1.7.7 above,
R5 is
1. a hydrogen atom,
2. xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.4 above,
3. xe2x80x94C(O)-R9, wherein R9 is
xe2x80x94NH2, xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.4, or xe2x80x94N(R13)2, wherein R13 is as defined in 1.7.7 above, or
4. xe2x80x94S(O)2-R9, wherein R9 is as defined in 3. above, or
R4 and R5 together with the atom to which they are bonded form a heterocycle, or
R3 and R5 together with the atom to which they are bonded form a heterocycle containing an additional oxygen atom in the ring and
R6, R7 and R8 independently of one another are chosen from hydrogen atom or methyl, or
in case b)
the substituents R1, R2 and R4 may be independently chosen as defined under 1.1 to 1.18 in case a) above,
R3 is
1. xe2x80x94CF3,
2. xe2x80x94CF2xe2x80x94CF3,
3. xe2x80x94CN,
4. xe2x80x94COOH,
5. xe2x80x94NO2,
6. xe2x80x94NH2,
7. xe2x80x94Oxe2x80x94(C1-C10)-alkyl, wherein alkyl is mono- to penta substituted by substituents independently chosen from
7.1 phenyl, which is unsubstituted or mono- to penta-substituted by substituents independently chosen from halogen or xe2x80x94Oxe2x80x94(C1-C4)-alkyl,
7.2 halogen,
7.3 xe2x80x94NH2,
7.4 xe2x80x94OH,
7.5 xe2x80x94COOR16, wherein R16 is hydogen atom or xe2x80x94(C1-C10)-alkyl,
7.6 xe2x80x94NO2,
7.7 S(O)yxe2x80x94R14, wherein y is zero, 1 or 2, R14 is xe2x80x94(C1-C10)-alkyl, phenyl, which phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, amino or xe2x80x94N(R13)2,
wherein R13 is independently of one another chosen from hydrogen atom, phenyl, xe2x80x94(C1-C10)-alkyl, xe2x80x94C(O)xe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)-phenyl, xe2x80x94C(O)xe2x80x94NHxe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)xe2x80x94O-phenyl, xe2x80x94C(O)xe2x80x94NH-phenyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C7)-alkyl, xe2x80x94S(O)yxe2x80x94R14, wherein R14 and y are defined as in 7.7,
and wherein the R13 alkyl or phenyl groups in each case are unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, or
R13 together with the nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
7.8 xe2x80x94O-phenyl, wherein phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
7.9 a radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine,
7.10 xe2x80x94(C3-C7)-cycloalkyl or
7.11 xe2x95x90O,
8. xe2x80x94N(R13)2, wherein R13 is as defined in 1.7.7 above,
9. xe2x80x94NHxe2x80x94C(O)xe2x80x94R15, wherein R15 is
9.1 a radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine,
wherein said radical is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, xe2x80x94CF3, benzyl or by xe2x80x94(C1-C10)-alkyl, wherein alkyl is mono to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
9.2 xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above or by xe2x80x94Oxe2x80x94C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
9.3 xe2x80x94(C3-C7)-cycloalkyl,
9.4 xe2x80x94N(R13)2, wherein R13 is as defined in 1.7.7 above, or
9.5 phenyl, wherein phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, by xe2x80x94Oxe2x80x94(C1-C10)-alkyl, by xe2x80x94CN, by xe2x80x94CF3, by xe2x80x94(C1-C10)-alkyl, wherein alkyl is mono to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above, or by two substituents of the phenyl radical which form a dioxolan ring
10. xe2x80x94S(O)yxe2x80x94R14 , wherein R14 and y are as defined in 1.7.7 above,
11. xe2x80x94C(O)xe2x80x94R12, wherein R12 is phenyl or xe2x80x94(C1-C7)-alkyl, wherein phenyl or alkyl are unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
12. xe2x80x94C(O)xe2x80x94Oxe2x80x94R12, wherein R12 is as defined in 11. above,
13. xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11 above,
14. xe2x80x94Oxe2x80x94(C1-C6)-alkyl-Oxe2x80x94(C1 -C6)-alkyl,
15. xe2x80x94Oxe2x80x94(C0-C4)-alkyl-(C3-C7)-cycloalkyl or
16. xe2x80x94(C1-C4)-alkyl-N(R13)2, wherein R13 is as defined in 1.7.7 above,
R5 is as defined as R5 in case a) above,
R6, R7 and R8 independently of one another are chosen from hydrogen atom or methyl.
Examples include compounds of formula I, wherein in case a)
B6, B7, B8, and B9 are each a carbon atom,
R1, R2 and R3 independently of one another are chosen from hydrogen atom, halogen, cyano, nitro, amino, xe2x80x94Oxe2x80x94(C1-C7)-alkyl, wherein alkyl is unsubstituted or substituted by phenyl, xe2x80x94CF2xe2x80x94CF3, xe2x80x94CF3, xe2x80x94N(R18)2, wherein alkyl is unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, or
xe2x80x94C(O)xe2x80x94Oxe2x80x94R12 is as defined above,
R6, R7 and R8 independently of one another are chosen from hydrogen atom or methyl, and
R5 is as defined as for case a) above,
or in case b)
the substituents R1, R2 and R4 independently of one another are hydrogen atom, halogen, cyano, nitro, amino, xe2x80x94Oxe2x80x94(C1-C7)-alkyl, wherein alkyl is unsubstituted or substituted by phenyl,
xe2x80x94CF2xe2x80x94CF3, xe2x80x94CF3, xe2x80x94N(R18)2,
wherein R18 is independently of one another chosen from hydrogen atom, xe2x80x94(C1-C7)-alkyl, phenyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl or xe2x80x94C(O)xe2x80x94(C1-C7)-alkyl, wherein each alkyl, pyridyl or phenyl are unsubstituted or mono- to tri-substituted independently of one another as defined under 1.7.1 to 1.7.11, or R18 together with the nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
S(O)yxe2x80x94R14,
wherein y is zero, 1 or 2, and R14 is xe2x80x94(C1-C10)-alkyl, phenyl, which phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, amino or xe2x80x94N(R18)2,
wherein R18 is as defined above,
wherein alkyl is unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, or
xe2x80x94C(O)xe2x80x94Oxe2x80x94R12, wherein R12 is as defined above,
R3 is cyano, nitro, amino, xe2x80x94Oxe2x80x94(C1-C7)-alkyl, wherein alkyl is substituted by phenyl, xe2x80x94CF2xe2x80x94CF3, xe2x80x94N(R18)2,
wherein R18 is independently of one another chosen from hydrogen atom, xe2x80x94(C1-C7)-alkyl, phenyl, xe2x80x94C(O)-phenyl, xe2x80x94C(O)-pyridyl, xe2x80x94C(O)xe2x80x94NH-phenyl, xe2x80x94C(O)xe2x80x94O-phenyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl or xe2x80x94C(O)xe2x80x94(C1-C7)-alkyl, wherein alkyl, pyridyl or phenyl are unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, or R18 together with the nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
S(O)yxe2x80x94R14,
wherein y is zero, 1 or 2, and R14 is xe2x80x94(C1-C10)-alkyl, phenyl, which phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, amino or xe2x80x94N(R18)2,
wherein R18 is as defined above,
xe2x80x83wherein alkyl is unsubstituted or mono- to tri-substituted independently of one another as defined under 1.7.1 to 1.7.11, or
xe2x80x94C(O)xe2x80x94Oxe2x80x94R12, wherein R12 is as defined as in 1.11 above,
R4 is cyano, amino, xe2x80x94Oxe2x80x94(C1-C7)-alkyl, wherein alkyl is substituted by phenyl;
xe2x80x94CF2xe2x80x94CF3, xe2x80x94CF3, xe2x80x94N(R18)2,
wherein R18 is independently of one another chosen from hydrogen atom, xe2x80x94(C1-C7)-alkyl, phenyl, xe2x80x94C(O)-phenyl, xe2x80x94C(O)-pyridyl, xe2x80x94C(O)xe2x80x94NH-phenyl, xe2x80x94C(O)xe2x80x94O-phenyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl or xe2x80x94C(O)xe2x80x94(C1-C7)-alkyl, wherein each alkyl, pyridyl or phenyl are unsubstituted or mono- to tri-substituted independently of one another as defined under 1.7.1 to 1.7.11, or R18 together with the nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
S(O)yR14,
wherein y is zero, 1 or 2, and R14 is xe2x80x94(C1-C10)-alkyl, phenyl, which phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, amino or xe2x80x94N(R18)2,
wherein R18 is as defined above,
wherein R18 is independently of one another chosen from hydrogen, atom,
xe2x80x94(C1-C7)-alkyl, phenyl, xe2x80x94C(O)-phenyl, xe2x80x94C(O)-pyridyl, xe2x80x94C(O)xe2x80x94NH-phenyl, xe2x80x94C(O)xe2x80x94O-phenyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl or xe2x80x94C(O)xe2x80x94(C1-C7)-alkyl, wherein each alkyl, pyridyl or phenyl are unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, or R18 together with the nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
S(O)yxe2x80x94R14,
wherein y is zero, 1 or 2, and R14 is xe2x80x94(C1-C10)-alkyl, phenyl,
which phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.11, amino or xe2x80x94N(R18)2,
wherein R18 is as defined above,
wherein alkyl is unsubstituted or mono- to tri-substituted independently of one another as defined under 1.7.1 to 1.7.11, or
xe2x80x94C(O)xe2x80x94Oxe2x80x94R12, wherein R12 is as defined above,
R6, R7 and R8 independently of one another are chosen from hydrogen atom or methyl, and
R5 is as defined above.
Further examples include compounds of formula (II) 
and/or a stereoisomeric form of the compound of the formula II and/or a physiologically tolerable salt of the compound of the formula II, wherein;
R1 and R2 are independently of one another chosen from hydrogen atom, halogen, cyano, amino, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, nitro, xe2x80x94CF3, xe2x80x94CF2xe2x80x94CF3, xe2x80x94S(O)yxe2x80x94R14,
wherein y is 1 or 2, R14 is amino, xe2x80x94(C1-C7)-alkyl or phenyl, which phenyl is unsubstituted or mono- to tri-substituted as defined for substituents under 1.7.1 to 1.7.11 above,
xe2x80x94N(R18)2, wherein R18 is independently of one another chosen from hydrogen atom, xe2x80x94(C1-C7)-alkyl-C(O)xe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)-phenyl, C(O)-pyridyl, xe2x80x94C(O)xe2x80x94NHxe2x80x94(C1-C4)-alkyl, xe2x80x94C(O)xe2x80x94O-phenyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl or xe2x80x94(C1-C10)-alkyl, wherein pyridyl, alkyl or phenyl are unsubstituted or mono- to tri-substituted independently of one another as defined under 1.7.1 to 1.7.11, or
R18 together with nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
R3 is cyano, amino, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, nitro, xe2x80x94CF3, xe2x80x94CF2xe2x80x94CF3, xe2x80x94S(O)yxe2x80x94R14 wherein y is 1 or 2, R14 is amino, xe2x80x94(C1-C7)-alkyl or phenyl, which phenyl is unsubstituted or mono- to tri-substituted as defined for substituents under 1.7.1 to 1.7.11 above,
xe2x80x94N(R18)2, wherein R18 is independently of one another chosen from hydrogen atom,
xe2x80x94(C1-C7)-alkyl-C(O)xe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)-phenyl, xe2x80x94C(O)-pyridyl,
xe2x80x94C(O)xe2x80x94O-phenyl, xe2x80x94C(O)xe2x80x94NHxe2x80x94(C1-C4)-alkyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl or
xe2x80x94(C1-C10)-alkyl, wherein pyridyl, alkyl or phenyl are unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under
1.7.1 to 1.7.11, or
R18 together with nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms, and
R5 is hydrogen atom, xe2x80x94(C1-C10)-alkyl,
wherein alkyl is unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under 1.7.1 to 1.7.4,
xe2x80x94C(O)xe2x80x94R9 or xe2x80x94S(O)2-R9, wherein
R9 is xe2x80x94(C1-C10)-alkyl, xe2x80x94Oxe2x80x94(C1-C10)-alkyl,
wherein alkyl is unsubstituted or mono- to tri-substituted independently of one another as defined under 1.7.1 to 1.7.4, or phenyl, which is unsubstituted or mono- to tri-substituted as defined under 1.7.1 to 1.7.11, or xe2x80x94N(R18)2, wherein R18 is as defined above.
Still further examples are compounds of formula (II), wherein
R1 is bromo, xe2x80x94CF3 or chloro,
R2 is hydrogen atom or Oxe2x80x94(C1-C2)-alkyl,
R3 is xe2x80x94N(R18)2, wherein R18 is independently of one another chosen from hydrogen atom, xe2x80x94Nxe2x80x94C(O)-pyridyl, xe2x80x94C(O)-phenyl, xe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)xe2x80x94(C1-C4)-alkyl or xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl, wherein alkyl or phenyl are unsubstituted or mono- to tri-substituted by substituents independently chosen from halogen or xe2x80x94Oxe2x80x94(C1-C2)-alkyl, and
R5 is hydrogen atom, methyl or xe2x80x94S(O)2xe2x80x94CH3.
Specific compounds and all pharmaceutically acceptable salts thereof which are illustrative of the compounds of the invention include the following; 
Further specific examples include the following compounds:
N-(6-Chloro-9H-xcex2-carbolin-8-yl)-nicotinamide, as well as the bismesylate salt, bistrifluoracetate salt and bishydrochloride salt of N-(6-Chloro-9H-xcex2-carbolin-8-yl)-nicotinamide, N-(6-Chloro-9H-xcex2-carbolin-8-yl)-3,4-difluoro-benzamide, as well as the hydrochloride salt of N-(6-Chloro-9H-xcex2-carbolin-8-yl)-3,4-difluoro-benzamide, N-(6-Chloro-7-methoxy-9H-xcex2-carbolin-8-yl)-nicotinamide as well as the bistrifluoracetate salt and bishydrochloride salt of N-(6-Chloro-7-methoxy-9H-xcex2-carbolin-8-yl)-nicotinamide and 6-Chloro-N-(6-chloro-9H-xcex2-carbolin-8-yl)-nicotinamide.
The term xe2x80x9calkylxe2x80x9d by itself or as part on another substituent, unless otherwise stated means a straight or branched chain hydrocarbon radical having 1 to 10 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary-butyl, pentyl, hexyl, heptyl, nonyl, octyl, decanyl or cycloalkyl having 3 to 7 carbon atoms such as cylopropyl, cyclobutyl, cyclohexyl or cycloheptyl.
The term xe2x80x9calkoxyxe2x80x9d by itself or as part on another substituent, unless otherwise stated means xe2x80x94O-alkyl or xe2x80x94O-substituted alkyl.
The term xe2x80x9cheterocycle having 5 to 7 ring atomsxe2x80x9d represents a radical of a monocyclic saturated system having 5 to 7 ring members, which contains 1, 2 or 3 heteroatoms as ring members. Examples of heteroatoms are N, O and S. Examples of the term heterocycle having 5 to 7 ring atoms are pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine.
The term xe2x80x9carylxe2x80x9d by itself or as part on another substituent, unless otherwise stated refers to an organic radical derived from an aromatic molecule by removal of one atom; such as phenyl, pyridyl, thiazoly, morpholinyl and naphthyl.
The term xe2x80x9csubstituted alkylxe2x80x9d means an alkyl radical substituted at one or more positions by one or more radicals of the group halogen, nitro, sulfo, amino, substituted amino, carboxyl, alkoxy, xe2x80x94O-aryl, xe2x80x94O-substituted aryl, and hydroxyl.
The term xe2x80x9csubstituted arylxe2x80x9d means an aryl radical substituted at one or more positions by one or more radicals of the group halogen, alkyl, substituted alkyl, nitro, sulfo, amino, alkoxy, aryl, substituted aryl, or hydroxyl groups, such as an aryl radical substituted at 1 to 3 positions by 1 to 3 groups.
The term xe2x80x9csubstituted aminoxe2x80x9d refers to xe2x80x94N(R13)2 wherein R13 is independently of one another chosen from hydrogen atom, sulfo, alkyl, aryl, xe2x80x94C(O)-alkyl, C(O)xe2x80x94NH-aryl, xe2x80x94C(O)xe2x80x94O-aryl, xe2x80x94C(O)xe2x80x94O-alkyl, or C(O)xe2x80x94O-aryl, wherein each alkyl or aryl may be independently substituted.
The term xe2x80x9csulfoxe2x80x9d refers to xe2x80x94S(O)yxe2x80x94R14, wherein R14 is an alkyl, aryl, substituted aryl, substituted alkyl, amino, or substituted amino and y is zero, one or two.
The term xe2x80x9chalogenxe2x80x9d is understood as meaning fluorine, chlorine, bromine or iodine.
The term xe2x80x9cxe2x80x94(C1-C4)-alkylxe2x80x9d is understood as meaning hydrocarbon radicals whose carbon chain is linear or branched and contains 1 to 4 carbon atoms.
The invention further relates to a process for the preparation of the compounds of formula I and/or stereoisomeric forms of the compounds of the formula I and/or physiologically tolerable salts of the compounds of formula I, which comprises
a) reacting a compound of formula III 
in which R1, R2, R3, R4, B6, B7, B8 and B9 are each as defined in formula I, with a compound of the formula IV, 
in the presence of a acid, to yield a compound of the formula V 
which is reacted with hydrazine hydrate and later with formaldehyde (R6 is H) or R6CHO to give a compound of formula VI 
and oxidized to give a compound of the formula VII, 
where R1 to R4, R6 to R8 and B6 to B8 are as defined in formula I, a compound of formula (I), or
b) a compound of the formula VII is reacted with a compound of the formula
Yxe2x80x94R5 (VIII)
where Y is halogen or xe2x80x94OH and R5 is as defined in formula I, to give a compound of the formula I, or
c) resolving a compound of the formula I, which on account of its chemical structure occurs in enantiomeric forms, prepared by process a) or b) into the pure enantiomers by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the diastereomers thus obtained, and removal of the chiral auxiliary groups, or
d) isolating the compound of the formula I prepared by process a), b) or c) either in free form or, in the case of the presence of acidic or basic groups, converting it into physiologically tolerable salts.
The preparation of physiologically tolerable salts of compounds of the formula I capable of salt formation, including their stereoisomeric forms, is carried out in a manner known per se. With basic reagents such as hydroxides, carbonates, hydrogencarbonates, alkoxides and also ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine or triethanolamine or alternatively basic amino acids, for example lysine, ornithine or arginine, the carboxylic acids form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts. If the compounds of the formula I contain basic groups, stable acid addition salts can also be prepared using strong acids. For this, both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylamidosulfonic, trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic or trifluoroacetic acid are suitable.
The invention also relates to pharmaceuticals which comprise an efficacious amount of at least one compound of the formula I and/or of a physiologically tolerable salt of the compounds of the formula I and/or an optionally stereoisomeric form of the compounds of the formula I, together with a pharmaceutically suitable and physiologically tolerable excipient, additive and/or other active compounds and auxiliaries.
On account of the pharmacological properties, the compounds according to the invention are suitable for the prophylaxis and therapy of all those disorders in whose course an increased activity of IkB kinase is involved. These include, for example, asthma, rheumatoid arthritis (in the case of inflammation), osteoarthritis, Alzheimer""s disease, carcinomatous disorders (potentiation of cytotoxic therapies), cardiac infarct or atherosclerosis.
The pharmaceuticals according to the invention are in general administered orally or parentally or by rectal, inhale or transdermal administration.
The invention also relates to the use of the compounds of the formula I 
and/or a stereoisomeric form of the compounds of the formula I and/or a physiologically tolerable salt of the compounds of the formula I,
for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of IkB kinase is involved,
wherein B6, B7, B8 and B9 are independently selected from the group consisting of carbon atom and nitrogen atom and wherein B6, B7, B8 and B9 together are no more than two nitrogen atoms at the same time;
where the substituents R1, R2, R3, R4 and R8 may be independently chosen from
1. hydrogen atom,
2. halogen,
3. xe2x80x94OH,
4. xe2x80x94CN,
5. sulfo,
6. xe2x80x94NO2,
7. xe2x80x94NH2,
8. alkoxy,
9. substituted amino,
10. xe2x80x94NHxe2x80x94C(O)xe2x80x94R15, wherein R15 is a heterocycle having 5 to 7 ring atoms, an alkyl, an aryl, a substituted aryl or a substituted alkyl,
11. xe2x80x94COOH,
12. xe2x80x94Oxe2x80x94R10, wherein R10 is alkyl, substituted alkyl or aryl,
13. xe2x80x94C(O)xe2x80x94R12, wherein R12 is alkyl, substituted alkyl or aryl,
14. xe2x80x94C(O)xe2x80x94Oxe2x80x94R12, wherein R12 is as defined in 13, above,
15. aryl,
16. xe2x80x94O-aryl,
17. substituted aryl,
18. xe2x80x94O-substituted aryl,
19. alkyl,
20. substituted alkyl,
21. xe2x80x94CF3 or
22. xe2x80x94CF2xe2x80x94CF3,
provided that at least one of R1, R2, R3, R4 and R8 is not a hydrogen atom,
R5 is
1. hydrogen atom,
2. alkyl,
3. alkyl radical, substituted at one or more positions by one or more of the radicals, halogen, amino or hydroxyl,
4. xe2x80x94C(O)xe2x80x94R9 or
5. xe2x80x94S(O)2xe2x80x94R9, in which
R9 is
a) alkyl,
b) alkyl radical, substituted at one or more positions by one or more of the radicals, halogen, amino or hydroxyl,
c) aryl,
d) aryl radical, substituted at one or more positions by one or more of the radicals, halogen, amino, or hydroxyl,
e) xe2x80x94NH2,
f) alkoxy or
g) substituted amino, and
R6 and R7 may be independently chosen from
1. hydrogen atom,
2. halogen,
3. xe2x80x94OH,
4. methyl,
5. xe2x80x94Oxe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to tri-substituted by substituents independently chosen from
5.1 aryl,
5.2 halogen,
5.3 xe2x80x94NO2,
5.4 sulfo,
5.5 xe2x80x94COOH,
5.6 xe2x80x94NH2,
5.7 xe2x80x94Oxe2x80x94(C1-C4)-alkyl or
5.8 xe2x80x94OH, or
6. xe2x80x94N(R13)2, wherein R13 is independently of one another chosen from hydrogen atom, aryl, xe2x80x94C(O)xe2x80x94(C1-C4)-alkyl or substituted aryl or alkyl, wherein said xe2x80x94C(O)xe2x80x94(C1-C4)-alkyl is unsubstituted or mono- to tri-substituted independently of one another as defined under 5.1 to 5.8, or
R13 together with the nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms.
Following are examples of the use of the compounds of formula I, wherein
B6, B7, B8, and B9 are each a carbon atom,
R1, R2, R3, R4 and R8 are independently chosen from
1. hydrogen atom,
2. halogen,
3. xe2x80x94CN,
4. xe2x80x94COOH,
5. xe2x80x94NO2,
6. xe2x80x94NH2,
7. xe2x80x94Oxe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from
7.1 phenyl, which is unsubstituted or mono- to penta-substituted by substituents independently chosen from halogen or xe2x80x94Oxe2x80x94(C1-C4)-alkyl,
7.2 halogen,
7.3 xe2x80x94NH2,
7.4 xe2x80x94OH,
7.5 xe2x80x94COOR16, wherein R16 is hydogen atom or xe2x80x94(C1-C10)-alkyl,
7.6 xe2x80x94NO2,
7.7 xe2x80x94S(O)yxe2x80x94R14, wherein y is zero, 1 or 2, R14 is xe2x80x94(C1-C10)-alkyl, phenyl, which phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.11, amino or xe2x80x94N(R13)2,
wherein R13 is independently of one another chosen from hydrogen atom, phenyl, xe2x80x94(C1-C10)-alkyl, xe2x80x94C(O)xe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)-phenyl, xe2x80x94C(O)xe2x80x94NHxe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)xe2x80x94O-phenyl, xe2x80x94C(O)xe2x80x94NH-phenyl, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C7)-alkyl, xe2x80x94S(O)yxe2x80x94R14 wherein R14 and y are as defined above,
and wherein R13 alkyl or phenyl groups in each case are unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.11 above, or
R13 together with the nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
7.8 xe2x80x94O-phenyl, wherein phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.11 above,
7.9 a radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine,
7.10 xe2x80x94(C3-C7)-cycloalkyl or
7.11 xe2x95x90O,
8. xe2x80x94N(R13)2, wherein R13 is as defined in 7.7 above,
9. xe2x80x94NHxe2x80x94C(O)xe2x80x94R15, wherein R15 is
9.1 a radical selected from pyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine,
wherein said radical is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.11 above, xe2x80x94CF3, benzyl or by xe2x80x94(C1-C10)-alkyl, wherein alkyl is mono to tri-substituted independently of one another as defined under 7.1 to 7.11 above,
9.2 xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.11 above or by xe2x80x94Oxe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.11 above,
9.3 xe2x80x94(C3-C7)-cycloalkyl,
9.4 xe2x80x94N(R13)2, wherein R13 is as defined in 7.7 above, or 9.5 phenyl, wherein phenyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.11 above, by xe2x80x94Oxe2x80x94(C1-C10)-alkyl, by xe2x80x94CN, by xe2x80x94CF3, by xe2x80x94(C1-C10)-alkyl, wherein alkyl is mono to tri-substituted by substituents independently chosen from those as defined under 7.1 to 7.11 above, or by two substituents of the phenyl radical which form a dioxolan ring,
10. xe2x80x94S(O)yxe2x80x94R14, wherein R14 and y are as defined in 7.7 above,
11. xe2x80x94C(O)xe2x80x94R12, wherein R12 is phenyl or xe2x80x94(C1-C7)-alkyl, wherein phenyl or alkyl are unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.11 above,
12. xe2x80x94C(O)xe2x80x94Oxe2x80x94R12, wherein R12 is as defined in 11, above,
13. xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.11 above,
14. xe2x80x94Oxe2x80x94(C1-C6)-alkyl-Oxe2x80x94(C1-C6)-alkyl,
15. xe2x80x94Oxe2x80x94(C0-C4)-alkyl-(C3-C7)-cycloalkyl,
16. xe2x80x94(C1-C4)-alkyl-N(R13)2, wherein R13 is as defined in 7.7 above
17. xe2x80x94CF3 or
18. xe2x80x94CF2xe2x80x94CF3,
provided that at least one of R1, R2, R3, R4 and R8 is not a hydrogen atom,
R5 is
1. hydrogen atom,
2. xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.4 above,
3. xe2x80x94C(O)xe2x80x94R9, wherein R9 is
xe2x80x94NH2, xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to penta-substituted by substituents independently chosen from those as defined under 7.1 to 7.4, or xe2x80x94N(R13)2, wherein R13 is as defined in 7.7 above, or
4. xe2x80x94S(O)2-R9, wherein R9 is as defined in 3 above,
or R4 and R5 together with the atom to which they are bonded form a heterocycle,
or R3 and R5 together with the atom to which they are bonded form a heterocycle containing an additional oxygen atom in the ring and
R6 and R7 independently of one another are chosen from hydrogen atom or methyl.
Further examples include the use of compounds of formula I for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of IkB kinase is involved, wherein
B6, B7, B8, and B9 are each a carbon atom,
R1, R2, R3 and R4 independently of one another are hydrogen atom, halogen, cyano, nitro, amino, xe2x80x94Oxe2x80x94(C1-C7)-alkyl, phenyl, xe2x80x94O-phenyl, xe2x80x94CF2xe2x80x94CF3, xe2x80x94CF3, N(R13)2,
wherein R13 is independently of one another chosen from hydrogen atom, xe2x80x94(C1-C7)-alkyl, phenyl, xe2x80x94C(O)-phenyl, xe2x80x94C(O)-pyridyl, xe2x80x94C(O)xe2x80x94NH-phenyl, xe2x80x94C(O)xe2x80x94O-phenyl, xe2x80x94C(O)xe2x80x94O-(C1-C4)-alkyl, xe2x80x94C(O)xe2x80x94(C1-C7)-alkyl or xe2x80x94(C1-C10)-alkyl, wherein alkyl, pyridyl or phenyl are unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under 7.1 to 7.11, or R13 together with nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
xe2x80x94S(O)yxe2x80x94R14,
wherein y is zero, 1 or 2, and R14 is xe2x80x94(C1-C10)-alkyl, phenyl, which phenyl is unsubstituted or mono- to penta-substituted as defined for substituents under 7.1 to 7.11, amino or xe2x80x94N(R13)2,
wherein R13 is as defined above,
wherein alkyl is unsubstituted or mono- to tri-substituted independently of one another as defined under 7.1 to 7.11, or
xe2x80x94C(O)xe2x80x94Oxe2x80x94R12, wherein R12 is as defined as in 11, above,
R6, R7 and R8 independently of one another are hydrogen atom, methyl, amino, xe2x80x94N(R13)2, wherein R13 is as defined above,
provided that at least one of R1, R2, R3, R4 and R8 is not a hydrogen atom, and
R5 is as defined immediately above.
Moreover, examples include the use of compounds of formula II 
and/or a stereoisomeric form of the compounds of the formula II and/or a physiologically tolerable salt of the compounds of the formula II, for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of IkB kinase is involved, wherein;
R1, R2 and R3 are independently chosen from hydrogen atom, halogen, cyano, amino, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, nitro, xe2x80x94CF3, xe2x80x94CF2xe2x80x94CF3, xe2x80x94S(O)yxe2x80x94R14 wherein y is 1 or 2,
R14 is amino, xe2x80x94(C1-C7)-alkyl, phenyl, which is unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under 7.1 to 7.9, or xe2x80x94N(R13)2, wherein
R13 is independently of one another chosen from xe2x80x94C(O)-pyridyl, hydrogenatom, xe2x80x94(C1-C7)-alkyl-C(O)xe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)-phenyl, xe2x80x94(C1-C10)-alkyl, xe2x80x94C(O)xe2x80x94NHxe2x80x94(C1-C4)-alkyl, xe2x80x94C(O)xe2x80x94O-phenyl or xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl, wherein
pyridyl, alkyl or phenyl are unsubstituted or mono- to tri-substituted independently of one another as defined under 7.1 to 7.11, or
R13 together with the nitrogen atom to which it is bonded form a heterocycle having 5 to 7 ring atoms,
provided that at least one of R1, R2 and R3 is not a hydrogen atom, and
R5 is hydrogen atom, xe2x80x94(C1-C10)-alkyl, wherein alkyl is unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under 7.1 to 7.4, xe2x80x94C(O)xe2x80x94R9 or xe2x80x94S(O)2xe2x80x94R9, wherein
R9 is xe2x80x94(C1-C10)-alkyl, xe2x80x94Oxe2x80x94(C1-C10)-alkyl,
wherein alkyl is unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under 7.1 to 7.4,
phenyl, which is unsubstituted or mono- to tri-substituted by substituents independently chosen from those as defined under 7.1 to 7.11, or xe2x80x94N(R13)2,
wherein R13 is as defined directly above.
Still further examples include the use of the compounds of formula II for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of IkB kinase is involved, wherein
R1, R2 and R3 are independently chosen from hydrogen atom, halogen, cyano, amino, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, nitro, xe2x80x94CF3 or N(R13)2,
wherein R13 is independently of one another chosen from hydrogen atom, xe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)xe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)-pyridyl, xe2x80x94C(O)-phenyl or xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl, wherein alkyl or phenyl are unsubstituted or mono- to tri-substituted by substituents independently chosen from halogen or xe2x80x94Oxe2x80x94(C1-C4)-alkyl, and
R5 is hydrogen atom, xe2x80x94C(O)xe2x80x94CH3, methyl, xe2x80x94S(O)2xe2x80x94CH3, xe2x80x94C(O)-morpholinyl, xe2x80x94CH2xe2x80x94CH2xe2x80x94OH or xe2x80x94CH2xe2x80x94C(O)xe2x80x94NH2,
provided that no more than two of R1, R2, R3 and R5 are a hydrogen atom. Further examples include the use of the compounds of formula II for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of IkB kinase is involved, wherein
R1 is bromo, xe2x80x94CF3 or chloro, R2 is hydrogen atom or Oxe2x80x94(C1-C2)-alkyl,
R3 is hydrogen atom, bromo, chloro or xe2x80x94N(R13)2,
wherein R13 is independently of one another chosen from hydrogen atom, xe2x80x94C(O)-phenyl, xe2x80x94(C1-C7)-alkyl, xe2x80x94C(O)xe2x80x94(C1-C4)-alkyl or xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl, wherein alkyl or phenyl are unsubstituted or mono- to tri-substituted by substituents independently chosen from halogen or xe2x80x94Oxe2x80x94(C1-C2)-alkyl, and
R5 is hydrogen atom, xe2x80x94C(O)xe2x80x94CH3, methyl or xe2x80x94S(O)2xe2x80x94CH3,
provided that no more than two of R1, R2, R3 and R5 are a hydrogen atom.
Specific examples include the use of the compounds of formula II for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of IkB kinase is involved, wherein
R1 is chloro, R2 and R3 are each hydrogen atom, and R5 is xe2x80x94C(O)xe2x80x94CH3, or
R1 is bromo, R2 and R3 are each hydrogen atom, and R5 is xe2x80x94C(O)xe2x80x94CH3, or
R1 is chloro, R3 is xe2x80x94Nxe2x80x94C(O)xe2x80x94CH2xe2x80x94Oxe2x80x94CH3 and R2 and R5 are each hydrogen atom, or
R1 is chloro, R3 is xe2x80x94Nxe2x80x94C(O)-para-fluoro-phenyl and R2 and R5 are each hydrogen atom, or R1 and R3 are each chloro, R2 is xe2x80x94C(O)xe2x80x94CH3 and R5 is hydrogen atom, or
R1 and R3 are each chloro, R5 is hydrogen atom and R2 is xe2x80x94C(O)xe2x80x94CH2xe2x80x94CH3.
On account of the pharmacological properties, the compounds according to the invention are suitable for the prophylaxis and therapy of all those disorders in whose course an increased activity of IkB kinase is involved. Disorders in whose course an increased activity of IkB kinase is involved include, for example the treatment of joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. Additionally, the compounds are useful in the treatment of acute synovitis, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter""s syndrome, endotoxaemia, sepsis, septic shock, endotoxic shock, gram negative sepsis, gout, toxic shock syndrome, chronic pulmonary inflammatory diseases including asthma and adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, carcinoses, leukemia, sarcomas, lymph node tumors, skin carcinoses, lymphoma, apoptosis, graft versus host reaction, allograft rejection and leprosy. Furthermore, the compounds are useful in the treatment of: infections such as viral infections, for example HIV, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, parasitic infections, for example malaria such as cerebral malaria, and yeast and fungal infections, for example fungal meningitis; fever and myalgias due to infection; AIDS; AIDS related complex (ARC); cachexia secondary to infection or malignancy; cachexia secondary to acquired immune deficiency syndrome (AIDS) or to cancer; keloid and scar tissue formation; pyresis; diabetes; and inflammatory bowel diseases such as Crohn""s disease and ulcerative colitis. The compounds of the invention are also useful in the treatment of diseases of or injury to the brain in which over-expression of TNFxcex1 has been implicated such as multiple sclerosis, and head trauma. The compounds according to the invention are also useful in the treatment of psoriasis, Alzheimer""s disease, carcinomatous disorders (potentiation of cytotoxic therapies), cardiac infarct, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).
The invention also relates to a process for the production of a pharmaceutical, which comprises bringing at least one compound of the formula I into a suitable administration form using a pharmaceutically suitable and physiologically tolerable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries.
Suitable solid or pharmaceutical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and preparations having protracted release of active compound, in whose preparation customary auxiliaries, such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavourings, sweeteners and solubilizers are used. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
The pharmaceutical preparations may be produced and administered in dose units, each unit containing as active constituent a certain dose of the compound of the formula I according to the invention. In the case of solid dose units such as tablets, capsules, coated tablets or suppositories, this dose can be up to approximately 1000 mg, such as from approximately 50 mg to 300 mg and in the case of injection solutions in ampoule form up to approximately 300 mg, such as from approximately 10 mg to 100 mg.
For the treatment of an adult patient weighing approximately 70 kg, depending on the efficacy of the compound according to formula I, daily doses of approximately 20 mg to 1000 mg of active compound, such as from approximately 100 mg to 500 mg, are indicated. Under certain circumstances, however, even higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else of a number of smaller dose units and by multiple administration of subdivided doses at specific intervals.
As a rule, final products are determined by mass-spectroscopic methods (FAB-, ESI-MS). Temperatures are given in degrees Celsius, RT means room temperature (22xc2x0 C. to 26xc2x0 C.). Abbreviations used are either explained or correspond to the customary conventions.
The following examples are numbered so as to correspond to the compounds of Table 1, below.